Ready-To-Use Carfilzomib Compositions

ABSTRACT

The present invention provides a stable, non-aqueous, ready-to-use parenteral composition comprising: carfilzomib or pharmaceutically acceptable salt thereof, acidifying agent, optionally a surfactant, one or more solvents or co-solvents.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.16/480,561 filed Jul. 24, 2019, which is a national phase entry under 35U.S.C. § 371 of International Application No. PCT/162017/052359, filedApr. 25, 2017, which claims priority from India Patent Application No.201741002669 filed Jan. 24, 2017, the disclosure of all of which areincorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a stable, non-aqueous, ready-to-useparenteral composition comprising: carfilzomib or pharmaceuticallyacceptable salt thereof, acidifying agent, optionally a surfactant, oneor more solvents.

BACKGROUND OF THE INVENTION

Carfilzomib is a peptide epoxy ketone derivative, chemically, it is atetra peptide epoxy ketone and an analog of epoxomicin. Carfilzomib iscommercially available as KYPROLIS® (Carfilzomib for Injection, which isa lyophilized formulation available as 30 mg/vial and 60 mg/vial asterile, white to off-white lyophilized powder and is available as asingle-use vial. Each 30 mg vial of KYPROLIS contains 30 mg ofCarfilzomib, 1500 mg sulfobutylether beta-cyclodextrin, and 28.9 mganhydrous citric acid, and each 60 mg vial contains 60 mg ofCarfilzomib, 3000 mg sulfobutylether beta-cyclodextrin, 57.7 mg citricacid, and sodium hydroxide for pH adjustment (target pH 3.5).

Due to stability issues, carfilzomib containing compositions must belyophilized before storage and reconstituted before use. Thereconstituted solution should be diluted further. The reconstituted ordiluted compositions are not stable and must be used within 24 hoursafter reconstitution. It requires initial reconstitution, two dilutionsprior to intravenous infusion and the same needs to be carried out underaseptic conditions.

Prior to administration, the KYPROLIS® (Carfilzomib) for Injection mustfirst be reconstituted with 29 mL and 15 mL of sterile water forinjection, which dilutes the amount of carfilzomib to 2 mg/mL, and thenfurther withdraw the calculated dose from the vial and diluted into 50mL using 5% dextrose Injection, USP intravenous bag.

The difficulties with the commercially available KYPROLIS® (Carfilzomib)formulation is complex administration process involving multiple steps.As described above, the person administering the drug must firstreconstitute the vial with sterile water for injection and thensubsequently transfer the reconstituted solution into an intravenousbag. While reconstituting, the medical practitioner must gently swirland/or invert the vial slowly for about 1 minute, or until completedissolution of any cake or powder occurs. The prescribing informationfor KYPROLIS® (Carfilzomib) for Injection gives clear instructions notto shake the vial to avoid foaming. Possibility of foaming duringreconstitution may pose risk of dosing error. A further difficulty ofthe KYPROLIS® (Carfilzomib) product is that the time duration fromreconstitution to administration must be completed in 24 hours. Furtherall the above mentioned reconstitution steps need to be carried out inaseptic conditions, making the process still difficult to follow.

U.S. Pat. No. 7,737,112 discloses pharmaceutical compositions ofpractically insoluble proteasome inhibitors. The compositions disclosedin this patent utilize cyclodextrin, water and organic solvents in orderto increase the solubility and stability of the practically insolubleproteasome inhibitors.

US patent application no. 20140073583 A1 discloses pharmaceuticalcompositions comprising peptide epoxy ketone, solvent suitable forinjection selected from group consisting ethanol, propylene glycol,polyethylene glycol and mixtures thereof, optionally water and anon-volatile sugar acid as a lyophilized composition. Also disclosed isa liquid composition of carfilzomib.

WO patent publication 2015198257 A1 discloses a stable carfilzomibinjection comprising carfilzomib or pharmaceutically acceptable saltsthereof with citric acid, tertiary butyl alcohol and water for injectionto obtain lyophilized product, wherein the said injection is free fromcyclodextrin derivatives; further the invention also discloses aready-to-use injection comprising carfilzomib, citric acid, dimethylacetamide and polysorbate 80, and the injection is free fromcyclodextrin derivatives.

WO patent publication 2016170489 A1 discloses pharmaceutical compositioncomprising carfilzomib or a pharmaceutically acceptable salt thereof, atleast one organic solvent such as dimethylacetamide or propylene glycolor ethanol, and a solubilizer such as hydroxy propyl beta-cyclodextrin(HPBCD), the composition further comprises citric acid, wherein saidcomposition has a water content of less than 2.5 percent w/w.

The marketed KYPROLIS® (Carfilzomib) product has many limitations, suchas long manufacturing procedure including drug dissolution and longlyophilization cycle to obtain the lyophilized product. Further thelyophilized product requires multiple dilutions and the reconstituted ordiluted composition develops frothing or foam formation, if proper careis not taken during reconstitution. If foam is formed, then the healthprofessional needs to wait 5 minutes until the foam subsides fromreconstituted solution. This is a cumbersome procedure and complicationto health care professionals. Carfilzomib has low aqueous solubility andhence considering the above drawbacks, surprisingly a stable,ready-to-use, parenteral composition of carfilzomib has been developedusing the non-aqueous environment which overcomes the above drawbacks.Further it does not require such cumbersome and expensive procedures oflyophilization, multiple dilutions and foaming.

SUMMARY OF THE INVENTION

The present invention relates to a stable, non-aqueous, ready-to-useparenteral composition comprising: carfilzomib or pharmaceuticallyacceptable salt thereof, acidifying agent, optionally a surfactant, oneor more solvents.

The composition according to above aspect, wherein the acidifying agentsinclude but not limited to sulphuric acid, hydrochloric acid,hydrobromic acid, phosphoric acid, ethanoic acid, boric acid,hydrofluoric acid, oxalic acid, nitric acid and the like;

-   surfactant include but not limited to polyoxyethylene sorbitan    esters (tweens), polyoxyethylene polyoxypropylene copolymers    (pluronics), sorbitan esters, lecithin, cremophor and mixtures    thereof;-   solvents include but not limited to glycols such as propylene    glycol, polyethylene glycol and the like; alcohols such as ethanol,    butanol, t-butanol; glycerol or its derivatives and mixtures    thereof;

Another aspect relates to a stable, non-aqueous, ready-to-use parenteralcomposition comprising:

-   i. carfilzomib or pharmaceutically acceptable salt thereof in a    concentration range of about of 1 mg/mL to about 20 mg/mL,-   ii. acidifying agent selected from ethanoic acid in a specific ratio    of about 1:1 and less than or equal to about 15:1,-   iii. optionally surfactants, and-   iv. solvents selected from propylene glycol, polyethylene glycol,    ethanol.

The composition according to preceding claims, the composition maycomprise other excipients such as antioxidants and/or preservativesoptionally.

The composition according to according to above aspect, wherein theratio of ethanoic acid to carfilzomib is between about 1.5:1 to about10:1.

The composition according to previous aspects, the composition is freeof cyclodextrins, water and non-volatile sugar acid.

The composition according to previous aspects, wherein the pH of thecomposition is from about 2 to about 9.

The non-aqueous composition according to preceding claims foradministering carfilzomib in patients in need thereof for the treatmentof multiple myeloma and related conditions.

One more aspect of the invention relates to the process for thepreparation of a composition, comprising:

-   -   a) add required quantity of ethanol in a manufacturing vessel        and add carfilzomib to it and stir to obtain a clear solution,    -   b) to the above vessel optionally other solvents propylene        glycol or polyethylene glycol, and optionally polysorbate or        sorbitan esters and optionally antioxidant may be added,    -   c) adjust the pH using suitable acidifying agent,    -   d) filter and fill the filtered solution into vials, stopper and        seal the vials and store the vials in suitable shipper,    -   e) inert gas such as nitrogen is used throughout the process to        reduce the risk of oxidation of carfilzomib.

DETAILED DESCRIPTION OF THE INVENTION

The term “composition” is intended to encompass a combination includingactive ingredients and pharmaceutically acceptable excipients, as wellas any product which results, directly or indirectly, from combination,complexation, or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions involving one or more of the ingredients.

The term “formulation” or “dosage form” or “composition” refers tofinished pharmaceutical products that are suitable for administration,including, but not limited to, injections, parenterals, etc.

The term “excipient” or “pharmaceutically acceptable excipient” or“adjuvant” means a component of a pharmaceutical product that is not apharmacologically active ingredient, such as fillers, diluents, carrier,solvents, co-solvents, preservatives, buffers, bulking agents, sugars,cellulose and its derivatives, pH modifiers, antioxidants, surfactants,isotonicity agents, etc, added to a drug to increase or aid its effect.The excipients or adjuvants that are useful in preparing pharmaceuticalcompositions are generally safe, non-toxic, and neither biologically norotherwise undesirable, and are acceptable for human pharmaceutical useas well as veterinary use. The term includes one or more excipients oradjuvants.

“Carrier” or “solvent” as used herein refers to pharmacologically inertmaterials that provide a more or less fluid matrix, suitable for topicaldrug administration. Carriers and solvents herein include any suchmaterials known in the art, which are nontoxic and do not interact withother components of a pharmaceutical composition or drug delivery systemin a deleterious manner. The compositions of the present invention areparticularly suitable for parenteral administration. Compositionssuitable for parenteral dosage forms such as injectable such asintravenous, intramuscular or subcutaneous, implants and the like. Otherparenteral ingredients used in the composition are generally thosecommonly used and recognized by persons skilled in the art of parenteralformulations.

The term “Carfilzomib” includes the compound carfilzomib,pharmaceutically acceptable salts, esters, solvates, hydrates orpolymorphs and the like thereof.

“Pharmaceutically-acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts, solvate, hydrate and the like thereof.Pharmaceutically-acceptable salt forms of compounds provided herein aresynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods.

The term “optional” or “optionally” means that the subsequentlydescribed element, component or circumstance may or may not be present,so that the description includes instances where the element, component,or circumstance is included and instances where it is not.

The term “stable” or “stability” as used herein includes both physicaland chemical stability. Stability parameters include but not limited topotency, related substances, stable pH value and other physico-chemicalparameters.

The term “about” when used in conjunction with a numeral here refers toa range of that numeral +/−10%, inclusive. However, alternativeconcentrations are also expressly deemed suitable for use herein.

Non-aqueous refers to the property of being free or substantially freeof water. However, this does not exclude the presence of residualamounts of water as commonly contained in non-aqueous organic liquidsand residual amounts of water contributed from the process ofmanufacturing composition, such as trace amounts of moisture present inmanufacturing vessels, tubing, filters and the like.

Any recitation of ranges of values set forth below is merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range, unless otherwise indicated herein, andeach separate value is incorporated into the specification as if it wereindividually recited herein. Furthermore, all references, includingpatent applications, cited herein are hereby incorporated by referenceto the same extent as if each reference were individually andspecifically indicated to be incorporated by reference and were setforth in its entirety herein.

The present invention relates to a stable, non-aqueous, carfilzomibready-to-use, parenteral composition, wherein the composition is free ofnon-volatile sugar acid, cyclodextrins and water.

The present composition can be prepared by combining carfilzomib,acidifying agent, and other excipients. The excipients include solvents,pH modifiers, preservatives, antioxidants, surfactant and the like ormixtures thereof.

The parenteral composition according to this invention wherein, examplesof solvents include but not limited to glycols such as propylene glycol,butylene glycol, polyethylene glycol; polyethylene glycol includepolyethylene glycol 300, polyethylene glycol 400 and the like; glycerolor its derivatives and mixtures thereof; dioxane, trioxane and othercyclic mono-, di- and tri-ethers, lower alkanols such as ethanol,propanol, isopropanol, sec-butanol, t-butyl alcohol (TBA), n-butylalcohol, ethyl acetate, acetone, acetonitrile, ethoxy ethanol, methanol,N-methyl-2-pyrrolidone, glycofurol, glycerol formal, tetrahydrofurfurylalcohol or other organic solvents and mixtures of suitable solventsthereof or their equivalents. Solvents or mixture or combination ofsolvents are used in a suitable proportion and suitable quantity toachieve desirable effect. Co-solvents may also be included in thepresent compositions and co-solvents include, but not limited to glycolssuch as propylene glycol, butylene glycol, polyethylene glycol and thelike, polyethylene glycol include polyethylene glycol 300, polyethyleneglycol 400 and the like; glycerol or its derivatives and mixturesthereof; dioxane, trioxane and other cyclic mono-, di- and tri-ethers,lower alkanols (such as ethanol, propanol, isopropanol, sec-butanol,t-butyl alcohol (TBA), n-butyl alcohol, ethyl acetate, acetone,acetonitrile, ethoxy ethanol, methanol, N-methyl-2-pyrrolidone,glycofurol, glycerol formal, tetrahydrofurfuryl alcohol or other organicsolvents and mixtures of suitable solvents.

In another aspect the pH of the composition plays a significant role tokeep the composition stable, pH of the present invention is from about 2to about 9; further pH modifications are contemplated with suitable pHmodifiers.

In one more aspect, by addition of acidifying agent to the composition,the pH of the composition was modified between about 2 to about 9 toobtain a clear stable solution after reconstitution.

The pH level for each pharmaceutical composition should be selected toprovide suitable solubility of the active ingredient used therein. It isgenerally preferred, however, that the pH of the compositions besuitable for injection and, therefore, will typically be between about2.0 and about 9.0. pH of the composition is modified to obtain a stablenon-aqueous composition using suitable pH modifiers. pH of the presentcomposition plays an important role in stabilizing the composition. Byaddition of acidifying agent to the composition, the pH of thecomposition was modified to obtain a clear stable solution afterreconstitution.

In another aspect, the compositions are stable when the composition isadded with pH modifiers, like acidifying agents. Examples of pHmodifiers include but not limited to acidifying agents, such as but notlimited to sulphuric acid, hydrochloric acid, phosphoric acid, ethanoicacid, boric acid, hydrofluoric acid, hydrobromic acid, oxalic acid,nitric acid or mixtures thereof. It is anticipated that upon addition ofpH modifiers the composition is physically and chemically more stablethan without those modifiers in the composition.

Further the composition may comprise of antioxidants and theantioxidants used in the compositions are optional. Examples ofantioxidants include but not limited to monothioglycerol,alpha-tocopherol, L-cysteine, thioglycolic acid, sodium metabisulfite(SMBS), ascorbic acid, sodium formaldehyde sulfoxylate, sodiumbisulfate, butylated hydroxy toluene (BHT), butylated hydroxy anisole(BHA) mixtures of combinations thereof.

In another aspect composition with antioxidants monothioglycerol,combination of butylated hydroxy toluene (BHT) and butylated hydroxyanisole (BHA), butylated hydroxy anisole (BHA), α-tocopherol,thioglycolic acid and composition without antioxidants were assessedusing inert gas environment precautions. Considering the chemicalstability with above antioxidants alpha-tocopherol, BHA and thioglycolicacid were found to be suitable in comparison with other antioxidants.

In another aspect the composition may comprise of surfactants. Examplesof surfactant include tweens, tweens include but not limited topolyoxyethylene sorbitan esters such as polysorbate 20 (Tween 20),polysorbate 40 (Tween 40), and polysorbate 80 (Tween 80);polyoxyethylene polyoxypropylene copolymers such as pluronics; sorbitanesters such as sorbitan monostearate, sorbitan tristearate, sorbitanmonolaurate and the like, lecithin, cremophor and mixtures thereof.Surfactants in the present compositions are optional and based on therequisite, the surfactants may be used.

The present invention may further comprise of other suitable excipientsother than the disclosed excipients, excipients may includepreservatives such as benzyl alcohol, thiomersal, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA) and the like or mixturesthereof.

The present invention relates to a stable, non-aqueous, carfilzomibready-to-use, parenteral composition, wherein the composition is free ofnon-volatile sugar acid, cyclodextrins and water.

The contemplated compositions are free of non-volatile sugar acid,cyclodextrins and water. Non-volatile sugar acid include citric acid,N-acetylneuraminic acid, N-acetyltalosaminuronic acid, aldaric acid,aldonic acid, 3-deoxy-D-manno-oct-2-ulosonic acid, galaturonic acid,D-galacturonic acid, glucaric acid, gluconic acid, glucuronic acid,glucono-gamma-lactone, glyceric acid, N-glycolylneuraminic acid,iduronic acid, isosaccharinic acid, lactobionic acid, mucic acid,muramic acid, neuraminic acid, pangamic acid, saccharic acid, sialicacid, threonic acid, ulosonic acid, uronic acid, X-Gluc, xylonic acid,ascorbic acid, mixtures thereof and other sugar acids, lactic acid,succinic acid, maleic acid, tartaric acid, salicylic acid, benzoic acid,methanesulfonic acid, oxalic acid, thioglycolic acid, and the like ormixtures thereof.

Cyclodextrins include alpha-, beta-, or gamma-cyclodextrins,beta-cyclodextrins include, hydroxy-alkyl beta-cyclodextrin,hydroxy-propyl-beta-cyclodextrin, sulfobutyl-ether-beta-cyclodextrin andthe like. Further, the composition is free or substantially free ofwater, however, this does not exclude the presence of residual amountsof water as commonly contained in non-aqueous organic liquids andresidual amounts of water contributed from the process of manufacturingcomposition, such as trace amounts of moisture present in manufacturingvessels, tubing, filters and the like. Therefore, the composition maycomprise trace amounts of water coming from above process.

In another aspect the present invention relates to a stable,non-aqueous, carfilzomib ready-to-use, parenteral composition, whereinthe composition comprises of:

-   i) carfilzomib or its pharmaceutically acceptable salts, solvates    and hydrates thereof,-   ii) acidifying agent selected from ethanoic acid in a specific ratio    of about 1:1 and less than or equal to about 15:1-   iii) solvents or co-solvents selected from propylene glycol,    polyethylene glycol, ethanol, and-   iv. optionally surfactants.

The non-aqueous solvent system includes, ethanol or propylene glycol orpolyethylene glycol, or a mixture of one or more solvents, ethanol andpropylene glycol; ethanol and polyethylene glycol; propylene glycol andpolyethylene glycol; ethanol, propylene glycol and polyethylene glycolor any mixtures or combinations thereof. The composition may alsocomprise propylene glycol or polyethylene glycol, glycerol, dioxane,alcohol and the like as co-solvents.

In another aspect, the parenteral composition accordingly hasconcentration of carfilzomib between about 1 mg/mL to about 20 mg/mL;for example, between about 4 mg/mL to about 16 mg/mL and between about 6mg/mL to about 12 mg/mL and composition is a ready-to-use composition.

In another aspect wherein the ratio of ethanoic acid to carfilzomib isbetween about 1:1 and less than or equal to about 15:1; for example, theratio is between about 1.5:1 to about 10:1; further the ratio is betweenabout 2:1 to about 8:1.

In another aspect the composition is free from lyophilization and thecomposition is a ready-to-use liquid solution, ready-to-use liquidconcentrate, ready-to-dilute liquid solution, ready-to-dilute liquidconcentrate and the like. A ready-to-use or ready-to-dilute liquidsolution or liquid concentrate is a composition that is suitable foradministration after dilution with a suitable diluent or physiologicalsolution.

In another embodiment, the present invention relates to a stable,non-aqueous, ready-to-use, parenteral composition, comprisingcarfilzomib or its pharmaceutically acceptable salt thereof, ethanol,propylene glycol or derivatives, or polyethylene glycol derivativesthereof, pH modifier, optionally antioxidants, and optionallysurfactants.

In another embodiment, the present invention relates to a stable,non-aqueous, ready-to-use, parenteral composition, comprisingcarfilzomib or its pharmaceutically acceptable salt thereof, ethanol,propylene glycol or derivatives thereof, polyethylene glycol 300 orpolyethylene glycol 400 or derivatives thereof, acidifying agent such asethanoic acid, optionally antioxidants and optionally surfactants.

In another embodiment, the present invention relates to a stable,non-aqueous, ready-to-use, parenteral composition, comprisingcarfilzomib or its pharmaceutically acceptable salt thereof, ethanol,propylene glycol or derivatives thereof, polyethylene glycol 300 orpolyethylene glycol 400 or derivatives thereof, ethanoic acid,optionally polysorbate 80 and optionally thioglycolic acid oralpha-tocopherol or mixtures thereof.

In another embodiment, the present invention relates to a stable,non-aqueous, ready-to-use, parenteral composition, comprisingcarfilzomib or its pharmaceutically acceptable salt thereof, ethanol,ethanoic acid, optionally polysorbate 80 and optionally thioglycolicacid or alpha-tocopherol or mixtures thereof.

In another embodiment, the present invention relates to a stable,non-aqueous, ready-to-use, parenteral composition, comprisingcarfilzomib or its pharmaceutically acceptable salt thereof, ethanol,optionally polysorbate 80, acidifying agent and optionally butylatedhydroxy toluene or butylated hydroxy anisole, or mixtures thereof.

In another embodiment, the present invention relates to a stable,non-aqueous, ready-to-use, parenteral composition, comprisingcarfilzomib or its pharmaceutically acceptable salt thereof, ethanol,optionally propylene glycol and/or polyethylene glycol 300 orpolyethylene glycol 400 or derivatives thereof, ethanoic acid,optionally polysorbate or sorbitan esters and optionally thioglycolicacid or alpha-tocopherol.

In another embodiment, the present invention relates to a stable,non-aqueous, ready-to-use, parenteral composition, comprisingcarfilzomib or its pharmaceutically acceptable salt thereof, ethanol,optionally propylene glycol, polyethylene glycol 300 or polyethyleneglycol 400 or derivatives thereof, thioglycolic acid oralpha-tocopherol, acidifying agent, optionally tweens or sorbitanesters, wherein the composition is free of non-volatile sugar acid,cyclodextrins and water.

In another embodiment, the present invention relates to a stable,non-aqueous, ready-to-use, parenteral composition, comprisingcarfilzomib or its pharmaceutically acceptable salt thereof, ethanol,optionally alpha-tocopherol, sulphuric acid, optionally tweens orsorbitan esters.

In another embodiment, the present invention relates to a stable,non-aqueous, ready-to-use, parenteral composition, comprisingcarfilzomib or its pharmaceutically acceptable salt thereof, ethanol,optionally alpha-tocopherol, ethanoic acid, optionally tweens orsorbitan esters.

In another embodiment, the present invention relates to a stable,non-aqueous, ready-to-use, parenteral composition, comprisingcarfilzomib or its pharmaceutically acceptable salt thereof, ethanol,optionally propylene glycol, optionally polyethylene glycol 300 orpolyethylene glycol 400 or derivatives thereof, optionallyalpha-tocopherol, ethanoic acid, optionally tweens or sorbitan esters,wherein the composition is free of non-volatile sugar acid,cyclodextrins and water.

In another embodiment, the present invention may further comprise ofother suitable excipients to make a stable non-aqueous composition,wherein the composition is free of non-volatile sugar acid,cyclodextrins and water.

In another embodiment this invention discloses a process to prepare theready-to-use stable parenteral composition which comprises of:

-   -   a) adding required quantity of ethanol in a manufacturing vessel        and add carfilzomib to it and stir to obtain a clear solution,    -   b) to the above vessel optionally other solvents propylene        glycol or polyethylene glycol, and optionally polysorbate or        sorbitan esters and optionally antioxidant may be added,    -   c) adjusting the pH using suitable acidifying agent,    -   d) filtering the solution, filling the filtered solution into        vials; stoppering and sealing the vials and storing the vials in        suitable shipper,    -   e) inert gas such as nitrogen is used throughout the process to        reduce the risk of oxidation of carfilzomib.

Sterilization can be achieved by gamma-irradiation, e-beam, naturallight, filtration, microwave heat sterilization such as moist heatsterilization. The sterilization may be steam sterilization or may beheat sterilization or filtration sterilization or a combination thereof.

In one embodiment, the present invention provides stable, ready-to-usecompositions which may be sterilized by filtration, heat sterilization,radiation (gamma-irradiation, electron beam, microwave) ethylene oxidesterilization and the like. Filtration is performed through filters withpore size ranging from 0.2 μm to 0.5 μm.

Regardless of the particular composition, it is preferred that thecomposition is packaged in a container suitable for single ormultiple-use. Such containers include an ampoule, vials, a pre-filledsyringe, an intravenous bag and the like. Multi-dose containers maycontain the carfilzomib in an amount suitable to allow one or moredistinct uses (based on the requirement to the user). Thus, preferredmulti-dose containers will be configured to contain a volume of thecomposition that is suitable for multiple and independentadministrations.

Carfilzomib with or without other therapeutically active agents may alsobe used in combination or prior to administering carfilzomib compositionwithout departing from the present invention or to prevent side effects(e.g., hypersensitivity reactions, gastrointestinal symptoms) associatedwith the administration of the inventive compositions. These agents mayoptionally be added to the compositions. Preferably the therapeuticallyactive agents synergistically enhance the effect of carfilzomib.Examples of therapeutic agents that may be used in conjunction with thepharmaceutical compositions of the present invention include, but arenot limited to alkylating agents, antihistamines, hormonal agents, H₂antagonists, plant-derived agents, biologic agents, thalidomides or itsderivatives, steroids or its derivatives, interleukins, interferons,cytokines, immuno-modulating agents, monoclonal antibodies, naturalproduct, anticancer agents, histone deacetylase inhibitors,antiretroviral agents, platinum-based drugs, and combinations thereof.

In one more embodiment the present invention relates to provide a stableready-to-use composition to treat patients in need thereof for thetreatment of multiple myeloma, lymphoma, leukemia, carcinoma or relatedconditions.

To further illustrate the invention, the following examples areprovided. It is to be understood that these examples are provided forillustrative purposes and are not to be construed as limiting the scopeof the invention. It is to be further understood that, in the examplesthe functions of individual ingredients are sometimes listed forillustration purposes.

EXAMPLES

Proposed carfilzomib compositions were developed and tested forfeasibility as semi-aqueous compositions, non-aqueous compositions withnon-volatile sugar acids, acidifying agent with or without anyexcipients to check the physico-chemical parameters and its stability.Semi-aqueous compositions were developed and found clear as such and ondilution with physiological solution thereby indicating physicalstability, hence these compositions were tested for chemical stability.However, semi aqueous compositions degraded in presence of water,observed known and unknown impurities were at higher side. Further itwas understood that composition containing aqueous portion may lead tohydrolysis, therefore it was concluded that compositions should be freefrom water. Hence non-aqueous compositions were developed and the sameare exemplified below:

Example 1: Non-Aqueous Compositions

NAQ1 NAQ2 NAQ3 NAQ4 NAQ5 SI. No Ingredients Quantity (mg/mL) 1.Carfilzomib 10 10  10 10 10 2. Ascorbic acid 3 — — — — 3. Citric acid —10  10 — — 4. PEG 300 350 300  300 — 150 5. Propylene Glycol Qs to 1 mL300 — 150 6. Polysorbate 80 — 100 300 — 7. Alpha-tocopherol — — 0.2 0.28. Ethanol — Qs to 1 mL Qs to 1 mL Qs to 1 mL

Example 1: Continued

NAQ6 NAQ7 NAQ8 NAQ9 SI. No Ingredients Quantity (mg/mL) 1. Carfilzomib 10  10 10 10 2. PEG 300 200 200 — 150 3. Propylene Glycol 200 200 — 1504. Polysorbate 80 100 300 100 300 5. Alpha-tocopherol — 0.2 0.2 6.Sulphuric acid Qs to pH — — 7. Ethanoic acid — Qs to pH 8. Ethanol Qs to1 mL Qs to 1 mL Qs to 1 mL

Considering the semi-aqueous compositions results, non-aqueouscompositions were developed to check the feasibility and stability ofsame.

Non-aqueous compositions NAQ1 comprising ascorbic acid were clear assuch initially and turned hazy later, hence NAQ1 compositions werediscontinued from further studies. Non-aqueous compositions NAQ2 andNAQ3 compositions comprising citric acid were clear initially and laterturned hazy, hence NAQ2 and NAQ3 compositions were discontinued fromfurther studies. NAQ4 & NAQ5 compositions devoid of any non-volatilesugar acid were developed and initially the compositions were clear andslowly developed haziness, forcing to discontinue with further studies.

Considering above observations on clarity of drug solution, few othercompositions were developed with acidifying agent such as sulphuricacid, ethanoic acid. NAQ6 and NAQ7 drug solution compositions withsulphuric acid and NAQ8, NAQ9 compositions with ethanoic acid were clearfor prolonged time and hence these compositions were considered forfurther studies.

Example 2: Compositions with Sulphuric Acid

AA1 AA2 AA3 AA4 AA5 AA6 AA7 SI. No Ingredients Quantity (mg/mL) 1.Carfilzomib 10  10  10  10  10  10  10 2. Propylene Glycol 150 200 200200 — — — 3. PEG 300 150 200 200 200 — — — 4. Polysorbate 80 300 100 200300 100 200 300 5. Alpha-tocopherol 0.2 — — — — — — 6. Sulphuric acid Qsto pH 7. Ethanol Qs to 1 mL

TABLE 2 Physical Observations Physio. solution description (mg/mL) WFI5% dextrose Composition Description 0.2 0.5 0.2 0.5 Remarks AA1 CS CS CSCS CS Physiological solution was clear free from particles AA2 CS LH HLH H Physiological solution turned hazy after dilution AA3 CS LH H LH HPhysiological solution was clear for two hours after dilution withcomposition AA4 CS CS CS CS CS Physiological solution was clear freefrom particles AA5 CS LH H LH H Physiological solution turned hazy afterdilution AA6 CS LH H LH H Physiological solution turned hazy afterdilution AA7 CS CS CS CS CS Physiological solution was clear free fromparticles

-   -   CS—Clear Solution; LH—Light Hazy; H—Hazy

Considering the drug solution clarity, compositions with sulphuric acidwere developed to check the stability. Example 3 discloses that fewproposed compositions containing sulphuric acid were clear, free fromthe particles and the pH was recorded towards acidic side a noteworthyindication. However physiological solution turned hazy after dilutionwith few other compositions containing less than or equal to 200 mg/mLpolysorbate 80. It was confirmed that propylene glycol and PEG 300content in the composition had negligible role to play. Hence AA1, AA4and AA7 compositions were considered for further stability studies.

Example 3—Compositions with Ethanoic Acid

AA8 AA9 AA10 AA11 AA12 AA13 AA14 SI. No Ingredients Quantity (mg/mL) 1.Carfilzomib 10 10 15 10 10 10 10 2. Polysorbate 80 — — — 400  500  200 300 3. Ethanoic acid — 150  30 10 20 30 30 4. Alpha-tocopherol — — — — —— 0.2 5. Ethanol Qs to 1 mL

Example 3—Continued

AA15 AA16 AA17 AA18 AA19 AA20 AA21 SI. No Ingredients Quantity(mg/mL) 1. Carfilzomib 10 10 20 20 20 10 20 2. Polysorbate 80 400  400 — — — 300 400 3. Ethanoic acid 30 50 50 100  150  30 30 4.Alpha-tocopherol — — — — — 0.2 0.2 5. Ethanol Qs to 1 mL

TABLE 3 Physical Observations Physio. solution description (mg/mL) WFI5% dextrose Composition Description 0.2 0.5 0.2 0.5 Remarks AA8 CS H H HH Immediately after dilution, clear solution turned hazy AA9 CS CS CS CSCS Physiological solution was clear free from particles after dilutionAA10 CS LH H LH H Physiological solution turned hazy after dilution AA11CS LH H LH H Physiological solution turned hazy after dilution AA12 CSLH H LH H Physiological solution turned hazy after dilution AA13 CS LH HLH H Physiological solution turned hazy after dilution AA14 CS LH H LH HPhysiological solution turned hazy after dilution AA15 CS CS CS CS CSPhysiological solution was clear free from particles after dilution AA16CS CS CS CS CS Physiological solution was clear free from particlesafter dilution AA17 CS CS CS CS CS Physiological solution turned hazyafter dilution AA18 CS CS CS CS CS Physiological solution turned hazyafter dilution AA19 CS CS CS CS CS Physiological solution turned hazyafter dilution AA20 CS CS CS CS CS Physiological solution was clear freefrom particles after dilution AA21 CS LH H LH H Physiological solutionturned hazy after dilution

The above examples were studied for optimizing ethanoic acid andpolysorbate 80 concentration in the composition to check the physicalstability after dilution with physiological solution. From the aboveobservations it was accomplished that the proposed compositions AA15 andAA16 with 10 mg/mL carfilzomib were clear and free from the particles,even after dilution with physiological solution. However, AA17, AA18,AA19 and AA21 compositions with 20 mg/mL carfilzomib concentration andwith or without polysorbate 80 were tested and all compositions turnedhazy on dilution with physiological solution thereby endorsing physicalinstability. Further AA10, 15 mg/mL concentration of carfilzomibcompositions also turned hazy, hence 15 mg/mL and 20 mg/mL compositionswere discontinued from further stability studies. Other compositionswith reduced ethanoic acid and polysorbate 80 concentration turned hazyafter dilution with physiological solution. Hence AA9, AA15, AA16 andAA20 compositions which were clear upon dilution with physiologicalsolution were considered for further studies.

Example 4- Impact of ethanoic acid quantity on Chemical stability EA1EA2 EA3 EA4 EA5 EA6 SI. No Ingredients Quantity (mg/mL) 1. Carfilzomib10 10 10 10 10 10 2. Polysorbate 80 300 300 300 300 300 300 3. PropyleneGlycol — — — — — — 4. PEG 300 — — — — — — 5. Alpha-tocopherol 0.2 0.20.2 0.2 0.2 0.2 6. Ethanoic acid 150 100 50 30 20 10 7. Ethanol Qs to 1mL

TABLE 4 Chemical Stability of EA1, EA2, EA3, EA4, EA5 and EA6compositions Parameters → Time EA1 EA2 EA3 EA4 EA5 EA6 Time Points(Days) Total Impurities (%) 60° C. 3 days 4.1 3.78 2.81 2.66 2.22 2.1

From the above example, 6 compositions EA1, EA2, EA3, EA4, EA5 and EA6were tested for stability with varying concentration of ethanoic acid atstress condition to know the stability, it was accomplished thatcompositions degradation is proportional to the quantity of ethanoicacid. Hence considering chemical stability parameters of abovecompositions, it was inferred that polysorbate 80 and ethanoic acidquantity needs to be optimized in order to stabilize the composition.Further, from the physical stability studies, it has been concluded thatAA9, AA15, AA16 and AA20 compositions were physically stable as theywere clear upon dilution with physiological solution. Therefore,considering chemical and physical stability outcome the, belowcomposition was optimized.

Example 5: Optimized Composition

SI. No Ingredients Quantity (mg/mL) 1. Carfilzomib 10 2. Polysorbate 80300 3. Alpha-tocopherol 0.2 4. PEG 300 100 5. Ethanoic acid 30 6.Ethanol Qs to 1 mL

TABLE 5 Chemical Stability of Optimized composition Parameters TimeTotal Impurities Time Points (Months) (%) T₀ T₀ 0.06 2-8° C. 1 M 0.0725° C./60 RH 1 M 0.43 40° C./75 RH 1 M 1.56

Based on the physicochemical stability details, composition of example 5were developed to optimize quantities of ethanoic acid required tostabilize the carfilzomib non-aqueous ready-to-use composition.Considering the above composition stability data, it is inferred thatcomposition degradation is proportional to the quantity of ethanoic acidin the composition.

Therefore, considering the above examples 1 to 5 it is accomplished thatoptimum quantity of ethanoic acid and optimum quantity of polysorbate 80is required for both physical and chemical stability of the non-aqueouscompositions, apart from other excipients in the compositions. Numeroustrials have been performed to determine the effect of ethanoic acidquantity on formulation stability and parallel physical stability withcombination of surfactant, from the physical stability data it wasconcluded that equal to or more than 30 mg ethanoic acid was required tokeep the diluted solution stable for at least 24 hours or more with thehelp of surfactant. The observed formulation degradation rate isdirectly propositional to the quantity of ethanoic acid in theformulation. However, surfactant did not show any significant impact onchemical stability, but played critical role on physical stability, theminimum quantity of surfactant 300 mg is required to keep the dilutedsolution clear for at least 24 hours and above with the help of ethanoicacid. However, ethanoic acid comprising compositions are comparable toeach other both physically and chemically thereby producing stable,ready-to-use, non-aqueous compositions.

The ready-to-use compositions are stable at 2° C. to 25° C., and roomtemperature for at least 3 months.

1. A composition comprising: carfilzomib or a pharmaceuticallyacceptable salt thereof in a range of about 1 mg/mL to about 20 mg/mL;ethanoic acid, wherein a ratio of the ethanoic acid to the carfilzomibis about 1:1 to about 15:1; at least one solvent; optionally asurfactant; and optionally an anti-oxidant, wherein the composition haspH from about 2 to about 9, wherein the composition is stable, ready touse, and substantially non-aqueous.
 2. The composition according toclaim 1, wherein the composition is substantially free of cyclodextrin.3. The composition according to claim 1, wherein the ratio of ethanoicacid to carfilzomib is about 1.5:1 to about 10:1.
 4. The compositionaccording to claim 1, wherein the ethanoic acid in the composition is inrange equal to or greater than 30 mg/mL to keep the composition stablefor at least 24 hours upon dilution.
 5. The composition according toclaim 1, wherein the at least one solvent comprises at least one of analcohol, a glycol, glycerol or a derivative thereof, and mixturesthereof.
 6. The composition according to claim 1, wherein the surfactantis at least one of a polyoxyethylene sorbitan ester, a polyoxyethylenepolyoxypropylene copolymer, a sorbitan ester, lecithin, cremophor, andmixtures thereof.
 7. The composition according to claim 1, wherein theanti-oxidant is at least one of monothioglycerol, alpha-tocopherol,L-cysteine, thioglycolic acid, sodium metabisulfite, ascorbic acid,sodium formaldehyde sulfoxylate, sodium bisulfate, butylated hydroxytoluene, butylated hydroxy anisole, or mixtures thereof.
 8. Thecomposition according to claim 5, wherein the solvent is a glycol whichis at least one of propylene glycol, polyethylene glycol, and mixturesthereof and the alcohol is at least one of ethanol, butanol, t-butanol,and mixtures thereof.
 9. The composition according to claim 1, whereinthe pH is from about 2 to about
 9. 10. The composition according toclaim 1, wherein the anti-oxidant is alpha-tocopherol; the surfactant isa polyoxyethylene sorbitan ester; and the solvent is glycerol, propyleneglycol, polyethylene glycol, ethanol, butanol, t-butanol, and mixturesthereof.
 11. The composition according to claim 1, wherein thecomposition is ready to dilute; is stable when stored at 25° C., 60%relative humidity for at least 1 month, is clear upon dilution with aphysiological solution and is stable when diluted for at least about 24hours.
 12. The composition of claim 1, wherein the composition issubstantially free of non-volatile sugar acid.
 13. A method for treatingmultiple myeloma and related conditions comprising administering thecomposition according to claim 1 in a parenteral dosage form.
 14. Acomposition comprising: carfilzomib or a pharmaceutically acceptablesalt thereof; ethanoic acid; and at least one solvent, wherein thecomposition is stable when stored at 25° C., 60% relative humidity forat least 1 month and the composition is ready to use and the compositionis clear upon dilution with physiological solution and stable for atleast about 24 hours.
 15. The composition according to claim 14, whereinthe carfilzomib or pharmaceutically acceptable salt thereof is in arange of about 1 mg/mL to about 20 mg/mL, wherein a ratio of theethanoic acid to the carfilzomib is about 1:1 to about 15:1.
 16. Thecomposition according to claim 14, wherein the ethanoic acid in thecomposition is in range equal to or greater than 30 mg/mL to keep thecomposition stable for at least 24 hours upon dilution.
 17. A method formanufacturing a composition, comprising; adding carfilzomib to ethanolto obtain a clear solution; and adding an acidifying agent includingethanoic acid to adjust a pH of the clear solution in a range from 2 to9 to form the composition, wherein a ratio of the ethanoic acid to thecarfilzomib is about 1:1 to about 15:1.
 18. The method of claim 17,wherein adding carfilzomib to ethanol further comprises: adding anadditional solvent to the clear solution, wherein the additional solventis at least one of propylene glycol, polyethylene glycol, polysorbate,or sorbitan easters.
 19. The method of claim 17, further comprising:adding an anti-oxidant to the clear solution, wherein the anti-oxidantis at least one of monothioglycerol, alpha-tocopherol, L-cysteine,thioglycolic acid, sodium metabisulfite, ascorbic acid, sodiumformaldehyde sulfoxylate, sodium bisulfate, butylated hydroxy toluene,butylated hydroxy anisole, and mixtures thereof.
 20. The method of claim17, further comprising: filtering the composition; and supplying aninert gas when manufacturing the composition.